Fatal breathing dysfunction in a mouse model of Leigh syndrome
Albert Quintana, … , Jan M. Ramirez, Richard D. Palmiter
Albert Quintana, … , Jan M. Ramirez, Richard D. Palmiter
Published June 1, 2012
Citation Information: J Clin Invest. 2012;122(7):2359-2368. https://doi.org/10.1172/JCI62923.
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Research Article Neuroscience

Fatal breathing dysfunction in a mouse model of Leigh syndrome

Abstract

Leigh syndrome (LS) is a subacute necrotizing encephalomyelopathy with gliosis in several brain regions that usually results in infantile death. Loss of murine Ndufs4, which encodes NADH dehydrogenase (ubiquinone) iron-sulfur protein 4, results in compromised activity of mitochondrial complex I as well as progressive neurodegenerative and behavioral changes that resemble LS. Here, we report the development of breathing abnormalities in a murine model of LS. Magnetic resonance imaging revealed hyperintense bilateral lesions in the dorsal brain stem vestibular nucleus (VN) and cerebellum of severely affected mice. The mutant mice manifested a progressive increase in apnea and had aberrant responses to hypoxia. Electrophysiological recordings within the ventral brain stem pre-Bötzinger respiratory complex were also abnormal. Selective inactivation of Ndufs4 in the VN, one of the principle sites of gliosis, also led to breathing abnormalities and premature death. Conversely, Ndufs4 restoration in the VN corrected breathing deficits and prolonged the life span of knockout mice. These data demonstrate that mitochondrial dysfunction within the VN results in aberrant regulation of respiration and contributes to the lethality of Ndufs4-knockout mice.

Authors

Albert Quintana, Sebastien Zanella, Henner Koch, Shane E. Kruse, Donghoon Lee, Jan M. Ramirez, Richard D. Palmiter

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Figure 4

Abnormal extra- and intracellular recordings of PreBötC of KO mice.

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Abnormal extra- and intracellular recordings of PreBötC of KO mice. (A–E...
(A–E) Simultaneous intracellular whole cell (lower trace, whole-cell voltage; Vm) and multi-unit population recordings (upper trace, integrated and rectified multi-unit recording; VRG) containing PreBötC from brain stem slices of KO and control mice in response to hypoxic conditions (95% N2/5% CO2, A). Intracellular recordings during fictive eupnea revealed a lower number of APs/burst (B) and a lower AP frequency (D) of KO mice (n = 8) compared with control mice (n = 5). In hypoxic conditions, control mice decreased to 56.96% ± 47.04% of baseline (C, n = 5), while KO mice (E, n = 8) stopped firing APs by the end of the 10-minute hypoxic exposure. (F) Population recordings of KO mice (n = 10) showed significantly (P < 0.05) reduced fictive gasping compared with control mice (n = 10). (G) Resting potential of inspiratory cells was not significantly different in slices from KO mice compared with control mice. Data points represent individual cells. (H) Example of a drive potential (upper trace, whole cell voltage; Vm) during a population burst (lower trace, integrated and rectified multi-unit recording of the VRG). (I) The depolarization in phase with the network burst was significantly reduced in slices from KO mice (5.51 ± 0.59 mV, n = 7) when compared with the control mice (10.13 ± 1.30 mV, n = 5, P = 0.005) under normoxic conditions. In addition, the KO mice had a severe reduction of the underlying depolarization when challenged by hypoxia (from 5.51 ± 0.59 to 0.52 ± 1.36 mV, n = 7, P = 0.0012), while the control mice did not show a significant reduction (10.13 ± 1.30 mV to 6.09 ± 6.43 mV). *P < 0.01. Data are shown as mean ± SEM.